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Antimicrobial Agents and Chemotherapy, July 2004, p. 2599-2603, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2599-2603.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antibacterial Effects of Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae Strains for Which MICs Are High, in an In Vitro Pharmacokinetic Model

Alasdair P. MacGowan,^* Alan R. Noel, Chris A. Rogers, and Karen E. Bowker

Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom

Received 18 December 2003/ Returned for modification 17 February 2004/ Accepted 17 March 2004

The antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection. Five strains of Streptococcus pneumoniae and two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used. The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (24). A high 10⁸ CFU/ml and low 10⁶ CFU/ml initial inocula were used. Employing the 24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC₅₀) for S. pneumoniae was in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum. For H. influenzae, the T>MIC EC₅₀ was 28 to 37%, and the 80% maximum response was 32 to 48% for the 24 measure and 20 to 48% for AUBKC. The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula. The S. pneumoniae data were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect. Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs. This is explained by the greater T>MICs of the enhanced formulation. Although resistant to amoxicillin-clavulanate by conventional breakpoints, S. pneumoniae and H. influenzae strains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate.

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* Corresponding author. Mailing address: Bristol Centre for Antimicrobial Research & Evaluation, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. Phone: 44(0)117 959 5651/2. Fax: 44(0)117 959 3154. E-mail: alasdair.macgowan{at}north-bristol.swest.nhs.uk.

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Antimicrobial Agents and Chemotherapy, July 2004, p. 2599-2603, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2599-2603.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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